The Androgen Receptor Centric Transcriptional Network in Prostate Cancer

Abstract

Transcriptional corepressors are commonly over-expressed in prostate cancers. However, their relationship with Androgen receptor (AR), the key transcription player governing prostate cancer biology, is largely unclear. Using ChIP-Seq, we generated the cistromes of AR, ERG, and several oncogenic transcriptional corepressors (HDAC1, HDAC2, HDAC3, and EZH2) in prostate cancer cells. Surprisingly, our results revealed an integrated androgen responsive AR-centric transcriptional network comprising of ERG, HDACs, and EZH2. Functionally, we showed the involvement of these transcriptional corepressors (HDAC1, HDAC2, HDAC3, and EZH2) in ERG-mediated repression of AR-induced genes that are associated with epithelial differentiation and are inhibitory to metastasis. Taken together, our results characterized and elucidated an interesting mechanism by which ERG, HDACs and EZH2 directly modulate the AR transcriptional output to impede epithelial differentiation and facilitate prostate cancer progression.